Protection from Lethal Coxsackievirus-Induced Pancreatitis by Expression of Gamma Interferon

Abstract

ABSTRACT Coxsackievirus infection causes severe pancreatitis and myocarditis in humans, often leading to death in young or immunocompromised individuals. In susceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglycemia. To investigate the potential of gamma interferon (IFN-γ) in protection and clearance of the viral infection, IFN-γ knockout mice and transgenic (Tg) mice specifically expressing IFN-γ in their pancreatic β cells were infected with CB4. Lack of IFN-γ in mice normally resistant to CB4-mediated disease resulted in hypoglycemia and rapid death. However, expression of IFN-γ in the β cells of Tg mice otherwise susceptible to lethal infection allowed for survival and protected them from developing the accompanying hypoglycemia. While all the mice had high levels of viral replication in their pancreata and comparable tissue pathology following viral infection, the Tg mice had significantly lower levels of virus at the peak of infection, significantly higher numbers of activated macrophages before and after infection, and less damage to their acinar tissue. Additionally, despite having increased levels of inducible nitric oxide synthetase (iNOS) expression, treatment of Tg mice with the iNOS inhibitor aminoguanidine did not alter the level of protection afforded by IFN-γ expression. In conclusion, IFN-γ protects from lethal coxsackievirus infection by activating macrophages in an iNOS-independent manner.